Liquid membrane artificial lung

ABSTRACT

An artificial lung is created by contacting liquid membrane encapsulated, oxygen containing gas bubbles with blood. The oxygen permeates the membrane rapidly going into the blood. The CO2 initially in the blood permeates the membrane going into the bubble where the initial CO2 partial pressure is lower. In this manner the blood is oxygenated and CO2 is simultaneously removed.

United States Patent 1191 Li et al.

[54] LIQUID MEMBRANE ARTIFICIAL LUNG [75 Inventors: Norman N. Li,Edisoni William J.

Asher, Fanwood, both of NJ [73] Assignee: Esso Research and EngineeringCompany, Linden, NJ.

221 Filed: Sept. 16,1970

21 Appl.No.: 72,851

[52] U.S. Cl. ..55/16, 55/53, 23/2585, 195/18 [51] Int. Cl. ..B0ld53/22, A61m C12b [58] Field of Search ..55/l6, 53, 158; 23/2585;195/l.8; 210/21, 22; 128/DIG. 3

[56] References Cited UNITED STATES PATENTS 11/1968 Li ..55/16 6/1970Rudlin ..195/1.8

[ 1 May 22, 1973 OTHER PUBLlCATIONS De Filippi et 51., 15655111: 61 aLiquid- Liquid Blood OXygenatOrJE WINIH), 1969, pp. 381491. Pitzele etal., A LiquidLiquid Oxygenator Utilizing Oxygen Saturated InertFluorocarbon for Organ Perfusion Preservation, Surgery, Vol. 68, No. 6,pp. 1079-1086, December, 1970.

' CAEN, June 16, 1969, p. 45.

Primary Examiner-Charles N. Hart Attorney-Chasan and Sinnock and MichaelConner [5 7 ABSTRACT In this manner the blood is oxygenated and CO issimultaneously removed.

12 Claims, No Drawings 1 LIQUID MEMBRANE ARTIFICIAL LUNG BACKGROUND OFTHE INVENTION This invention pertains to a process for oxygenatingmammalian and preferably human blood while simultaneously removingcarbon dioxide from the blood. More particularly, this inventionpertains to a process for oxygenating human blood and removing carbondioxide from such blood by contacting the blood with oxygen containingbubbles; said bubbles are coated with a liquid membrane which isolatesthe blood from gaseous oxygen. The liquid membrane encompass the gaspreventing a blood-gas interface while allowing oxygen to diffuse intothe blood and allowing the carbon dioxide to diffuse from the blood tothe separate gas phase. In a preferred embodiment of the instantinvention the membrane is a fluorocarbon or a derivative thereof andencompasses a gas which is substantially oxygen. Fluorocarbonderivatives include those surface active fluorocarbons which arehalogenated e.g. chlorinated, except those which are fluorinated,oxygenated e.g. fluoroethers and those which contain metal ions e.g.Na,Mg.

Currently, the incidence of lung disease in the United States isincreasing at a very rapid rate. Emphysema and similar diseases in whichthe body fails to properly oxygenate the blood cause a tremendous strainon the heart and this eventually in many cases leads to premature death.To increase the oxygen within the bloodstream several artificial lungshave been developed. The best commercial artificial lung devices operateby contacting blood directly with oxygen.

Unfortunately, these devices are expensive and have met with limitedsuccess. More significantly, they have had the problem of bloodhemolysis or the rupture of red blood cells and of the denaturation ofproteins in the blood. Proteins consist of up to several million units.These proteins that are soluble in water, or in blood, form colloidalsolutions. Fundamental change of their needed characteristic propertiescan easily occur by surface contacting with oxygen or some non compatible solid surface and also by chemical treatments. Such fundamentalchange of proteins characteristic properties is termed denaturation.

Thus a method is needed by means of which blood can be efficientlyoxygenated, while C0,, is simultaneously removed from the system, in theabsence of denaturation.

SUMMARY OF THE INVENTION According to this invention it has unexpectedlybeen found that contacting liquid membrane encapsulated bubbles ofoxygen with venous blood will serve to effectively remove the carbondioxide from the blood and add oxygen to the blood. When this balance isdestroyed because of illness or other cause, the patient may lapse intounconsciousness and eventual death. It is obvious that even temporarylack of oxygen will result in permanent damage of brain cells.

To reoxygenate the blood according to the process of the instantinvention the following procedure is followed.

Bubbles of oxygen containing gas are formed in the liquid which is toform the liquid membrane. These bubbles are then allowed to migrate to ablood liquid interface. The bubbles then enter the venous blood phasebecause the bubbles have a lower density compared to blood. When thesebubbles enter the blood they have a liquid membrane film aroundther'n'pjr e; venting a damaging blood gas interface. The liquidmembrane encapsulated droplets areallowed to move through the bloodunder the influence of their lower density. As they move through theblood oxygen diffuses through the liquid membrane to the blood therebyoxygenating it. A concomitant diffusion of carbon dioxide from thevenous blood to the gas bubble also occurs. Thus the blood is changedfrom the venous state which is carbon dioxide rich, oxygen depleted tocarbon dioxide lean, oxygen replenished with the adjustment of operatingparameters be made to match that of arterial blood. This blood is thenready to reenter the patient to support homeostatis.

The liquid membrane incapsulated bubbles move through the blood underthe influence of their density difference and agglomerate forming a foamcontaining very little of any blood. This foam-blood interfaceeffectively prevents a damaging blood-gas interface. With time thebubbles in the foam collapse liberating the gas while in somewhatdepleted in oxygen and enhanced in carbon dioxide content. This gas canthen be discarded by venting. A separate vessel is normally provided forthe collapsing of the foam so the liquid membrane which is thecontinuous phase of the foam will not on breaking form small dropletsthat mightbe admixed with the blood. The continuous phase of the foamafter it has collapsed can be collected and reused to make additionalliquid membrane. I,

The venous blood can either be treated on a batch basis or on acontinuous basis. When a continuous process is used the blood flow canbe primarily downward, countercurrent to rising liquid membraneencapsulated bubbles. I V

In more detail the instant invention pertains to a method foroxygenating blood and in particular venous blood while removing carbondioxide from the blood. Venous blood is the blood which is returning tothe heart after having transported oxygen to various parts of the body.Thus, the blood has a lower concentration of oxygen than the blood whichhas been pumped directly from the heart into the arteries. In addition,venous blood has absorbed carbon dioxide from the tissues so the contentof carbon dioxide in venous blood is higher than carbon dioxide contentof blood within the arteries. Normally, venous blood contains about 53volume percent of carbon dioxide and about 15 volume percent of oxygen.

In the case of lung disease the oxygen content of the blood has to beenriched since the lungs are not capable of bringing in the desiredamount of oxygen which would be in the amount of about 20 volume percentin the arterial blood. Also, carbon dioxide has to be removed tomaintain a normal 50 volume percent in the arterial blood. Thus, theinstant invention pertains to a system in which additional oxygen isforced into the blood while carbon dioxide is removed. To do this theblood is shunted from the body and passed through a system in which itis oxygenated while carbon dioxide is removed. The system contains gasbubbles, said bubbles being coated with a liquid membrane comprisingfluorocarbon or their derivatives and their solvent. Within the bubblesis a gas with a higher oxygen partial pressure than in the venous bloodand a low carbon dioxide pressure than in the blood. The membrane allowsoxygen to diffuse into the blood and carbon dioxide to diffuse into thebubble.

7 Advantages of the instant invention are readily apparent: blooddenaturation is avoided because the proteins in blood are not in directcontact with bulk oxygen. The presence of a liquid membrane serves as abarrier between blood and oxygen, and oxygen only gets into the bloodstream by molecular diffusion through the liquid membrane. The COremoval occurs because of the low CO partial pressure in the bubble. Inaddition, the very small bubble size presents a large transfer area forthe O and CO with an accompanying increase in efficiency and rate.

The contacting of the emulsion and the blood may take place in manyways. One way is to contact them in a tower with countercurrent flow.The blood may be the continuous phase and the encapsulated bubbles aredispersed uniformly throughout the blood phase both by the way it isintroduced into the column and by the flow existing in the column.

The bubbles collapse into a foam at the top of the column. This foam istransported to a separate vessel where it collapses. The collapsedliquid membrane film can then be recycled and used to make additionalmembrane.

The surfactants which may be utilized include the long-chain polarsurfactants such as the fluorocarbons, and their derivatives, the fluorohydrocarbons and their derivatives, silicones, and miscellaneoussurfactants such as polymeric surfactants. By derivatives it is meanthalogenated derivatives, except fluorine; e.g. chlorine, oxygenatedderivatives such as ethers and metallic derivatives such as Na and Mg.Any chemical compounds that fulfill the following criteria can be usedas a surfactant in this invention:

1. High surface activity so that gas droplets can be formed when a gasis introduced and mixed with a solution of the surfactant in afluorocarbon, or its derivative, solvent.

2. Insignificant solubility in water so that it does not dissolve in anysignificant amount in either'blood or the CO absorbent solution.

3. Good compatibility with blood so that blood will not be damaged orpoisoned by contacting the liquid membranes it forms.

The most preferred surfactants for the instant invention are theshort-chain fluorocarbons which are usually within the carbon number(per molecule) from to 20. There are a variety of such compoundsavailable in the market, notably, those manufactured by 3M Company, suchas FC-43 etc., and those manufactured by DuPont and marketed under thename of Freon E Series.

Typically, such fluorocarbons have five to, 20 carbons, preferably 10 tocarbons.

Specific fluorocarbons which are most preferred are the following;fluorinatcd C ether, manufactured by DuPont as E-4, perfluorotributylamine,'manufactured by 3M as FC-43 and other fluorocarbon compoundsmanufactured by 3M such as FCI76, FX-l84, etc.

The bubbles are formed by introducing an oxygen containing gas into asolution of fluorocarbons and/or their derivatives at intensive mixingcondition or by using high velosity jots of gas. The bubble size formedis between l0 and 5 X l0 cm preferably between 5 X 10' and 10' cm.

The partial pressure of oxygen in this gas is between 90 and 1,000 mmHg. The carbon dioxide pressure of this gas is below 40 mm Hg.Preferably the gas is humidified so that the partial pressure of waterin the gas is equal to the water partial pressure of the blood at thetemperature it is being oxygenated. The oxygenation may take placebetween 4 and 40 C preferably between 35 and 40 C.

Next the gas bubbles are allowed to move through the fluorocarbon and/ortheir derivatives to a blood interface. Here the bubbles move into theblood carrying a liquid membrane surrounding the bubble into the bloodphase. The liquid membrane encapsulated droplets move up because oftheir lower density countercurrent to the downward flowing blood.

The liquid membrane encapsulated bubbles move to the top of the bloodphase and coalesce forming a foam. This foam prevents a gas-bloodinterface on top of the blood. The fluorocarbon which had been theliquid membrane when the bubbles were in the blood phase forms thecontinuous phase of the foam. Under some operating conditions this foammay include blood in small quantities.

This foam is then transferred to another vessel where it is allowed tobreak down with time. The rate of break down may be accelerated by suchstandard technique as ultra sonics if desired. Four phase tend to formin this vessel. The top phase is the spent gas from the oxygenationwhich has reduced oxygen content and enhanced carbon dioxide content.This gas may be vented. Below the gas phase is the gas in fluorocarbonfoam phase. This phase isolates a blood phase collecting below it fromthe potentially damaging gas phase. This quantity of blood usingapproved operating procedures will be very small in comparison to thequantity of blood oxygenated in the primary oxygenation zone. This bloodwhich is oxygenated has been protected from ablood-gas interface so itmay be recirculated to the patient. The lowest phase is the fluorocarbonsolution which can be recycled and used to make liquid membranes again.

Typically the blood which is introduced to the oxygenator has an oxygenpartial pressure of 40 mm Hg. and the blood withdrawn mm Hg oxygenpartial pressure. Similarly the carbon dioxide partial pressure of theblood introduced is about 46 mm carbon dioxide partial pressure and thatwithdrawn about/l0 mm Hg. carbon dioxide partial pressure.

SPECIFIC EMBODIMENTS was introduced to the bottom of a tube and theblood put on top of it. A stainless steel tube with about a 5 mm insidediameter was put into the fluorocarbon phase and oxygen introducedthrough this orifice at a rate of about 40 cc/min.

Bubbles formed in the fluorocarbon phase and rose into the blood phasecarrying an encapsulating liquid membrane with them. The oxygen contentof the blood was monitored with a physiological gas analysis with anoxygen electrode manufactured by Beckman Corpora' tion.

The blood oxygen content measured in mm Hg oxygen partial pressure roserapidly as the experiment proceeded as shown in the table below.

Samples of blood were submitted for a hemoglobin in in plasmatest afterthe experiment was completed. No hemoglobin could be detected in theplasma. In contrast a blank run was made without the fluorocarbonsolution bubbling the oxygen directly into the blood which of courseformed the damaging blood-gas interface. In this blank run thehemoglobin in plasma increased 8 percent indicating blood damage fromthe blood-gas interface. The absence of hemoglobin in plasma in theexperiment using fluorocarbon indicates the liquid membrane protectedthe blood preventing red cell breakdown.

In the above experiment using fluorocarbon a foam collected on top ofthe blood; this foam was allowed to overflow into another containerwhere it broke down with time. The liquids from the collapsed foam wereblood and fluorocarbon. The blood weight was only 2 grams showingmoderate blood inclusion in the foam even under the arbitrarily shownconditions. The fluorocarbon collected from this foam weighed grams. Thecollection of fluorocarbon from this position in the apparatus isconclusive proof that a liquid membrane was forming around the bubblesas this is the only way the denser fluorocarbon could get to thiselevated position.

What is claimed is:

l. A process for oxygenating mammalian blood which comprises contactingsaid blood with oxygen containing gas bubbles, said bubbles being coatedwith a liquid membrane, said membrane permitting the permeation ofoxygen into the blood whereby at least a portion of said oxygen passesthrough said membrane and into said blood, and removing said liquidmembrane as a foam comprising gas bubbles coated with said liquidmembrane.

2. The process of claim 1 wherein said membrane is a fluorocarbon or aderivative thereof.

3. The process of claim I wherein the concentration gradient of the COin the blood is higher than in said bubble and at least a portion of theCO in said blood passes into said bubble.

4. The process-of claim 3 wherein said membrane is a fluorinated surfaceactive ether.

5. The process of claim 3 wherein said membrane is a C to Cfluorocarbon.

6. A process for oxygenating human blood and removing carbon dioxidefrom said blood which comprises contacting said blood with gas bubblessaid bubbles being coated with a liquid surfactant membrane andencompassing oxygen said membrane permitting the passage of oxygen intothe bloodstream, maintaining a higher partial pressure of carbon dioxidein said bloodstream than in said bubble whereby oxygen permeates throughsaid membrane into said bloodstream and carbon dioxide permeates intosaid bubble and removing a foam comprising carbon dioxide enrichedbubbles.

7. The process of claim 6 wherein said surfactant is a surface activefluorocarbon.

8. The process of claim 7 wherein said fluorocarbon is a fluorinatedsurface active ether.

9. The process of claim 7 wherein said fluorocarbon is a C to Cfluorocarbon.

10. The process of claim 6 wherein said contacting takes place at atemperature of 4 to 40 C.

11. The process of claim 6 wherein the contact between said blood andsaid bubbles is countercurrent.

12. A process for oxygenating blood and simultaneously removing carbondioxide which comprises placing in a blood oxygenating zone, bloodhaving an excess of carbon dioxide and insufficient oxygen dissolvedtherein, and a liquid membrane forming solution, said liquid membraneforming solution comprising a fluorinated surfactant, and characterizedas being immiscible with said blood and of sufficiently higher densitythan said blood, whereby said blood and said liquid membrane solutionform two continuous immiscible phases, said blood being disposed abovesaid liquid membrane forming solution and in contact with said liquidmembrane forming solution, and introducing oxygen bubbles into saidliquid membrane forming solution at a rate sufficient to form a foam,said foam being characterized as oxygen bubbles surrounded by liquidmembranes, said liquid membranes being permeable to both oxygen andcarbon dioxide, whereby said foam rises into said blood and oxygenpermeates from said foam into said blood and carbon dioxide permeatesfrom said blood into said foam.

I i i 4'

2. The process of claim 1 wherein said membrane is a fluorocarbon or aderivative thereof.
 3. The process of claim 1 wherein the concentrationgradient of the CO2 in the blood is higher than in said bubble and atleast a portion of the CO2 in said blood passes into said bubble.
 4. Theprocess of claim 3 wherein said membrane is a fluorinated surface activeether.
 5. The process of claim 3 wherein said membrane is a C5 to C15fluorocarbon.
 6. A process for oxygenating human blood and removingcarbon dioxide from said blood which comprises contacting said bloodwith gas bubbles said bubbles being coated with a liquid surfactantmembrane and encompassing oxygen said membrane permitting the passage ofoxygen into the bloodstream, maintaining a higher partial pressure ofcarbon dioxide in said bloodstream than in said bubble whereby oxygenpermeates through said membrane into said bloodstream and carbon dioxidepermeates into said bubble and removing a foam comprising carbon dioxideenriched bubbles.
 7. The process of claim 6 wherein said surfactant is asurface active fluorocarbon.
 8. The process of claim 7 wherein saidfluorocarbon is a fluorinated surface active ether.
 9. The process ofclaim 7 wherein said fluorocarbon is a C5 to C15 fluorocarbon.
 10. Theprocess of claim 6 wherein said contacting takes place at a temperatureof 4* to 40* C.
 11. The process of claim 6 wherein the contact betweensaid blood and said bubbles is countercurrent.
 12. A process foroxygenating blood and simultaneously removing carbon dioxide whichcomprises placing in a blood oxygenating zone, blood having an excess ofcarbon dioxide and insufficient oxygen dissolved therein, and a liquidmembrane forming solution, said liquid membrane forming solutioncomprising a fluorinated surfactant, and characterized as beingimmiscible with said blood and of sufficiently higher density than saidblood, whereby said blood and said liquid membrane solution form twocOntinuous immiscible phases, said blood being disposed above saidliquid membrane forming solution and in contact with said liquidmembrane forming solution, and introducing oxygen bubbles into saidliquid membrane forming solution at a rate sufficient to form a foam,said foam being characterized as oxygen bubbles surrounded by liquidmembranes, said liquid membranes being permeable to both oxygen andcarbon dioxide, whereby said foam rises into said blood and oxygenpermeates from said foam into said blood and carbon dioxide permeatesfrom said blood into said foam.